Acid esters Michael addition, intramolecular

During the coverage period of this chapter, reviews have appeared on the following topics reactions of electrophiles with polyfluorinated alkenes, the mechanisms of intramolecular hydroacylation and hydrosilylation, Prins reaction (reviewed and redefined), synthesis of esters of /3-amino acids by Michael addition of amines and metal amides to esters of a,/3-unsaturated carboxylic acids," the 1,4-addition of benzotriazole-stabilized carbanions to Michael acceptors, control of asymmetry in Michael additions via the use of nucleophiles bearing chiral centres, a-unsaturated systems with the chirality at the y-position, and the presence of chiral ligands or other chiral mediators, syntheses of carbo- and hetero-cyclic compounds via Michael addition of enolates and activated phenols, respectively, to o ,jS-unsaturated nitriles, and transition metal catalysis of the Michael addition of 1,3-dicarbonyl compounds. ... 

Enamine addition to an unsaturated ester, followed by an intramolecular alkylation, provided a facile synthesis of an adamantane bis-/3-ketoester 674). Michael addition of pyrrolidinocycloheptene to other acrylic esters 668) and of other enamines to acrylic acids 675), a chloroacrylonitrile 676), and an unsaturated cyanocarboxamide (577) were reported. 

Triphenylphosphine gives Michael additions to the activated triple bond of acetylene dicarboxylic esters in presence of acidic compounds HY (Scheme 1). The reactions take place easily at room temperature, even at -10°C [1], through formation of intermediate activated vinylic phosphonium salts, which undergo a subsequent Michael addition of HY. The reactions afford various stabilized ylides which can be isolated in high yields or undergo possibly evolution, for example by intramolecular Wittig reaction [2]. 

Hydroxamic acids constitute an important class of siderophores, which play a major role in iron solubilization and transport. Some of them are important as therapeutic agents. The Michael addition of nitroacetyl proline esters to allyl acrylate followed by Pd(0)-catalyzed intramolecular allyl transfer and subsequent reduction of the nitro group yields a novel class of cyclic hydroxamic acids related to pyroglutamic acid (Scheme 5.9).85... 

In addition, we were able to extend the tandem hetero Michael addition/a-ester-enolate alkylation protocol by an intramolecular variant via a Michael-initiated ring closure (MIRC) reaction leading to diastereo- and enantiomerically pure trans-configured 2-amino-cycloalkanoic acids 30 (Scheme 1.1.7) [14c,d]. 

Intramolecular conjugate allylation (12, 25).2 Fluoride ion catalyzes intramolecular Michael additions of allyltrimethylsilane to a,p-enones as well as a,p-unsaturated esters, nitriles, and amides Lewis acid catalysis is not effective. The method is particularly suited to cyclopentane annelations.2... 

Condensation of fumaric acid chloride monoethyl ester 147 with aminoalcohol 146, followed by intramolecular Michael addition of the isolated amide 148, afforded the l,4-benzoxazepine-3-acetate 149. The thermodynamically favored 3,5-tram-isomers were obtained (Scheme 21) <2002BMC385, 2002BMC401, 2002JME4571>. 

The selective nucleophilic displacement of one ortho nitro group from 2,4,6-trinitrotoluene by esters of mercap-toacetic acid followed by oxidation leads to 2-(alkoxycarbonyl)methylsulfonyl compounds. These sulfones react with aromatic aldehydes under Knoevenagel conditions to produce thiochroman 1,1-dioxides 477, probably via a stilbene and a subsequent intramolecular Michael addition. Activating groups other than nitro are compatible with the route (Scheme 167) <2003RJ0397>. 

Fig (8) The transformation of lactone (53) to keto ester (58) is described. The unsaturated aldehyde (59) is converted to tricyclic ketone (60) by two steps (Michael addition, and intramolecular aldol condensation). And this on subjection to aromatization and hydrogenation respectively leads the formation of (62) whose transformation to (+)0-methyl pisiferic acid (2) is accomplished by methylation and hydrolisis. 

An intramolecular Michael addition has been used to effect transformation of the pyrrole 50 to the indolizidine 51, the ester group of which was later homologated by a one-carbon unit, and the acid so obtained underwent in turn an intramolecular acylation at the pyrrole C-3 giving the tricyclic structure 52, which eventually lead to a formal total synthesis of ( )-aspidospermidine after a few additional steps <02JCS(P1)2613>. 

Disubstituted flavanones and chromanones are produced with good enantioselectivity from chalcones activated by an a-fert-butyl ester function through an intramolecular Michael addition catalysed by a chiral thiourea derivative. In situ decarboxylation enhances the ee and yields remain high <07JA3830>. A comprehensive study of the asymmetric cyclisation of 2 -hydroxychalcones to flavanones has refuted the ability of camphorsulfonic acid to achieve enantioselectivity but has shown that cinchona-based catalysts can be effective <07EJO5886>. 

As in the uncatalyzed reactions with enamines (vide supra), there is potentially more than one point where stereochemical differentiation can occur (Scheme 59). Selectivity can occur if the initial addition of the enol ether to the Lewis acid complex of the a,/J-unsaturated acceptor (step A) is the product-determining step. Reversion of the initial adduct 59.1 to the neutral starting acceptor and the silyl enol ether is possible, at least in some cases. If the Michael-retro-Michael manifold is rapid, then selectivity in the product generation would be determined by the relative rates of the decomposition of the diastereomers of the dipolar intermediate (59.1). For example, preferential loss of the silyl cation (or rm-butyl cation for tert-butyl esters step B) from one of the isomers could lead to selectivity in product construction. Alternatively, intramolecular transfer of the silyl cation from the donor to the acceptor (step D) could be preferred for one of the diastereomeric intermediates. If the Michael-retro-Michael addition pathway is rapid and an alternative mechanism (silyl transfer) is product-determining, then the stereochemistry of the adducts formed should show little dependence on the configuration of the starting materials employed, as is observed. 

Substituted pyrrole-2-carboxylic esters 19 are synthesized from A-tolylsulfonyl glycine ester 17 and vinyl ketones Kenner synthesis) [42]. By Michael addition and intramolecular aldol addition, they first yield pyrrolidine-2-carboxylic esters 18. These are converted into pyrroles by succesive H2O and sulfmic acid eliminations. 

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